Structural and dynamical characterization of pRb, LTSV40 and the pRb-LTSV40 complex suggests a common mechanism for pRb inactivation
IntroductionThe retinoblastoma protein (pRb) is a key regulator of the cell cycle that suppresses cell proliferation by binding to E2F transcription factors. Disruption of this pathway, commonly through mutations or interactions with viral oncoproteins, can lead to uncontrolled cell growth and cance...
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Frontiers Media S.A.
2025-04-01
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| author | Carla Luciana Padilla Franzotti Carla Luciana Padilla Franzotti Nicolas Palopoli Nicolas Palopoli Juliana Palma Juliana Palma Gustavo Pierdominici-Sottile Gustavo Pierdominici-Sottile |
| author_facet | Carla Luciana Padilla Franzotti Carla Luciana Padilla Franzotti Nicolas Palopoli Nicolas Palopoli Juliana Palma Juliana Palma Gustavo Pierdominici-Sottile Gustavo Pierdominici-Sottile |
| author_sort | Carla Luciana Padilla Franzotti |
| collection | DOAJ |
| description | IntroductionThe retinoblastoma protein (pRb) is a key regulator of the cell cycle that suppresses cell proliferation by binding to E2F transcription factors. Disruption of this pathway, commonly through mutations or interactions with viral oncoproteins, can lead to uncontrolled cell growth and cancer. The large T antigen of simian virus 40 (LTSV40) is known to bind pRb, thereby inhibiting its interaction with E2F transcription factors. However, the structural and dynamic mechanisms underlying this inhibition remain incompletely understood.MethodsWe employed molecular dynamics (MD) simulations, principal component analysis, and cluster analysis to investigate the conformational dynamics of pRb, LTSV40, and their complex. Our study focused on an intrinsically disordered region on the C-terminal side of the LFCSE motif of LTSV40, referred to as Linker 1.ResultsOur simulations reveal that Linker 1 undergoes a significant conformational shift upon binding to pRb. While this region adopts a predominantly bent structure in the unbound state, it transitions into an extended conformation in the complex. As a consequence of this change, the C-terminal segment of LTSV40 obstructs access to the AB-cleft of pRb, the binding site for E2F.DiscussionOur findings suggest that the inactivation mechanism of pRb by LTSV40, as unveiled by MD simulations, could represent a broader strategy employed by other viral oncoproteins containing similar LXCXE motifs and adjacent disordered regions. This mechanism may even extend to endogenous pRb inactivation. As our conclusions are based on computational modeling, they require experimental validation. Such confirmation would pave the way for developing therapeutic strategies aimed at reactivating pRb function in pathologies where it is compromised. |
| format | Article |
| id | doaj-art-121905a8f06f49b8bf83638918f8ba64 |
| institution | OA Journals |
| issn | 2813-530X |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Chemical Biology |
| spelling | doaj-art-121905a8f06f49b8bf83638918f8ba642025-08-20T02:12:06ZengFrontiers Media S.A.Frontiers in Chemical Biology2813-530X2025-04-01410.3389/fchbi.2025.15383501538350Structural and dynamical characterization of pRb, LTSV40 and the pRb-LTSV40 complex suggests a common mechanism for pRb inactivationCarla Luciana Padilla Franzotti0Carla Luciana Padilla Franzotti1Nicolas Palopoli2Nicolas Palopoli3Juliana Palma4Juliana Palma5Gustavo Pierdominici-Sottile6Gustavo Pierdominici-Sottile7Departamento de Ciencia y Tecnología, Universidad Nacional de Quilmes, Buenos Aires, ArgentinaConsejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Ciudad Autónoma de Buenos Aires (CABA), Buenos Aires, ArgentinaDepartamento de Ciencia y Tecnología, Universidad Nacional de Quilmes, Buenos Aires, ArgentinaConsejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Ciudad Autónoma de Buenos Aires (CABA), Buenos Aires, ArgentinaDepartamento de Ciencia y Tecnología, Universidad Nacional de Quilmes, Buenos Aires, ArgentinaConsejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Ciudad Autónoma de Buenos Aires (CABA), Buenos Aires, ArgentinaDepartamento de Ciencia y Tecnología, Universidad Nacional de Quilmes, Buenos Aires, ArgentinaConsejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Ciudad Autónoma de Buenos Aires (CABA), Buenos Aires, ArgentinaIntroductionThe retinoblastoma protein (pRb) is a key regulator of the cell cycle that suppresses cell proliferation by binding to E2F transcription factors. Disruption of this pathway, commonly through mutations or interactions with viral oncoproteins, can lead to uncontrolled cell growth and cancer. The large T antigen of simian virus 40 (LTSV40) is known to bind pRb, thereby inhibiting its interaction with E2F transcription factors. However, the structural and dynamic mechanisms underlying this inhibition remain incompletely understood.MethodsWe employed molecular dynamics (MD) simulations, principal component analysis, and cluster analysis to investigate the conformational dynamics of pRb, LTSV40, and their complex. Our study focused on an intrinsically disordered region on the C-terminal side of the LFCSE motif of LTSV40, referred to as Linker 1.ResultsOur simulations reveal that Linker 1 undergoes a significant conformational shift upon binding to pRb. While this region adopts a predominantly bent structure in the unbound state, it transitions into an extended conformation in the complex. As a consequence of this change, the C-terminal segment of LTSV40 obstructs access to the AB-cleft of pRb, the binding site for E2F.DiscussionOur findings suggest that the inactivation mechanism of pRb by LTSV40, as unveiled by MD simulations, could represent a broader strategy employed by other viral oncoproteins containing similar LXCXE motifs and adjacent disordered regions. This mechanism may even extend to endogenous pRb inactivation. As our conclusions are based on computational modeling, they require experimental validation. Such confirmation would pave the way for developing therapeutic strategies aimed at reactivating pRb function in pathologies where it is compromised.https://www.frontiersin.org/articles/10.3389/fchbi.2025.1538350/fullpRbE2FLTSV40retinoblastoma proteinviral oncoproteinsMD simulations |
| spellingShingle | Carla Luciana Padilla Franzotti Carla Luciana Padilla Franzotti Nicolas Palopoli Nicolas Palopoli Juliana Palma Juliana Palma Gustavo Pierdominici-Sottile Gustavo Pierdominici-Sottile Structural and dynamical characterization of pRb, LTSV40 and the pRb-LTSV40 complex suggests a common mechanism for pRb inactivation Frontiers in Chemical Biology pRb E2F LTSV40 retinoblastoma protein viral oncoproteins MD simulations |
| title | Structural and dynamical characterization of pRb, LTSV40 and the pRb-LTSV40 complex suggests a common mechanism for pRb inactivation |
| title_full | Structural and dynamical characterization of pRb, LTSV40 and the pRb-LTSV40 complex suggests a common mechanism for pRb inactivation |
| title_fullStr | Structural and dynamical characterization of pRb, LTSV40 and the pRb-LTSV40 complex suggests a common mechanism for pRb inactivation |
| title_full_unstemmed | Structural and dynamical characterization of pRb, LTSV40 and the pRb-LTSV40 complex suggests a common mechanism for pRb inactivation |
| title_short | Structural and dynamical characterization of pRb, LTSV40 and the pRb-LTSV40 complex suggests a common mechanism for pRb inactivation |
| title_sort | structural and dynamical characterization of prb ltsv40 and the prb ltsv40 complex suggests a common mechanism for prb inactivation |
| topic | pRb E2F LTSV40 retinoblastoma protein viral oncoproteins MD simulations |
| url | https://www.frontiersin.org/articles/10.3389/fchbi.2025.1538350/full |
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